Sulfonamide-containing indole compounds

ABSTRACT

The present invention creates a novel antiangiogenic agent and provides an antitumor agent which shows high safety as compared with conventional antitumor agents, has a sure effect and is able to be administered for a long period. That is, it provides an indole compound represented by the following formula (I), its pharmacologically acceptable salt or hydrates thereof.                    
     In the formula, R 1  represents hydrogen atom, a halogen atom or cyano group; R 2  and R 3  are the same as or different from and each represents hydrogen atom, a C 1 ˜C 4  lower alkyl group or a halogen atom; R 4  represents hydrogen atom or a C 1 ˜C 4  lower alkyl group; and the ring A represents cyanophenyl group, aminosulfonylphenyl group, aminopyridyl group, aminopyrimidyl group, a halopyridyl group or cyanothiophenyl group, provided that the case where all of R 1 , R 2  and R 3  are hydrogen atoms, where both R 2  and R 3  are hydrogen atoms or where the ring A is aminosulfonyl group and both R 1  and R 2  are halogen atoms is excluded. Further, when the ring A is cyanophenyl group, 2-amino-5-pyridyl group or a 2-halo-5-pyridyl group and R 1  is cyano group or a halogen atom, at least one of R 2  and R 3  should not be a hydrogen atom.

This application is the national phase under 35 U.S.C. § 371 of PCTInternational Application No. PCT/JP00/01071 which has an Internationalfiling date of Feb. 24, 2000, which designated the United States ofAmerica.

FIELD OF THE INVENTION

The present invention relates to a sulfonamide-containing indolecompound and to an antiangiogenic effect thereof. More particularly, itrelates to an antitumor agent, a cancer metastasis suppressor, atherapeutic agent for diabetic retinopathy, a therapeutic agent forrheumatic arthritis and a therapeutic agent for hematoma on the basis ofan antiangiogenic effect.

PRIOR ART

It has become clear that there is a close relation between proliferationof cancer and angiogenesis. Thus, when angiogenesis is not generated atthe site of cancer, the cancer remains in a state of dormant tumor.However, it has become clarified that, when angiogenesis is generated,oxygen and nutrients in blood are supplied to the tumor wherebyproliferation and metastasis of cancer are promoted resulting in aclinically malignant state. Accordingly, it is expected that, whenangiogenesis of cancer is suppressed, proliferation and metastasis ofcancer can be suppressed. Since angiogenetic vessels are composed ofendothelial cells and interstitial cells of the host, target of theantiangiogenic agent is not cancer cells but such normal cells of thehost. Because of the fact that the cancer cells are not a direct target,efficacy to the cancer which does not respond to known anticancer agentscan be expected as well and, in addition, it is presumed that thepossibility of occurrence of tolerant cancer which is a big problem incancer therapy is little. In addition, angiogenesis is a tumor-specificphenomenon and, in mature individuals, it is limited to the formation ofendometrium, etc. accompanied by a menstrual cycle. Accordingly, itsadverse effect is thought to be little as compared with known anticancerdrugs. Recently, it has been experimentally proved in preclinical teststhat antiangiogenic agents are able to suppress and further to reducethe proliferation of cancer in the cancer-transplanted models and thattolerant cancer is not generated and, in clinical tests, the correlationbetween angiogenesis and malignization of many solid cancers such asbreast cancer, prostatic cancer, lung cancer and cancer of the colon hasbeen shown.

In cancer tissues, apoptosis and proliferation of cancer cellscontinuously occur and it has been known that, depending upon thebalance between them, progressive cancer or dormant tumor results. Anantiangiogenic agent does not directly kill the cancer cells but cutsoff the nutrient sources so that the said balance is inclined toapoptosis inducing dormant tumor or reduction in cancer whereby it is adrug which can be expected to exhibit an excellent effect (prolongationof life, inhibition of recurrence and suppression of metastasis) by along-term therapy.

In a preclinical stage, there are antiangiogenic agents by variousaction mechanisms but, since their antitumor effect in a preclinicalstage is insufficient, their usefulness in clinical stage is stilldoubtful and, therefore, there has been a brisk demand forantiangiogenic agents where the effect is reliable.

It has been also known that angiogenesis participates in retinopathy orretinitis. When blood vessel is proliferated in retina, eyesight getsworse and, when progressed, blindness is resulted. There has been noeffective therapeutic drug therefor at present and effective therapeuticdrugs have been demanded.

WO 9301182 discloses antitumor agents due to a specific tyrosine kinaseinhibiting activity of the compounds having an indole skeleton but theyare indolylmethylene-2-indolinone compounds and are different from thepresent invention. Similarly, WO 964016 discloses an antitumor agent dueto a specific tyrosine kinase inhibiting activity of the compoundshaving an indole skeleton but they are 2-indolinone-3-methylenecompounds and are different from the present invention. Sulfonamidecompounds having an indole structure are disclosed in JP-A 7-165708 andJP-A 8-231505. However, the compounds which are specifically disclosedin JP-A 7-165708 and have two substituents other than aryl (orheteroaryl) sulfonylamino group on an indole ring are limited andcombinations of those substituents are only six, i.e. (1) 3-Cl and 4-Cl;(2) 3-Cl and 4-OCH₃; (3) 3-Cl and 4-OH; (4) 3-Cl and 4-CH₃; (5) 3-Cl and4-CN; and (6) 3-CN and 5-Br. There is no combination of (a) 3-CN and4-CH₃; (b) 3-Cl and 5-Br; (c) 3-Cl and 4-Br; and (d) 3-Br and 4-CH₃.With regard to 4-halogen monosubstituted compounds, there is adescription for 4-Br compounds but its sulfonyl moiety is ap-nitrophenol compound only. Further, indole compounds disclosed in JP-A8-231505 are 3-halogen or 3-cyano monosubstituted compounds only. Inthose laid-open publications, there is no description for anantiangiogenic effect at all and there is no description suggesting thatas well.

DISCLOSURE OF THE INVENTION

An object of the present invention is to create a novel antiangiogenicagent and to provide an antitumor agent which shows a high safety and asure effect as compared with conventional antitumor agents and is ableto be administered for a long period.

The present inventors have carried out an intensive study, found thatthe sulfonamide-containing indole compound represented by the followingformula achieves the aimed object and accomplished the presentinvention. That is, the present invention relates to asulfonamide-containing indole compound represented by the followingformula (I), its pharmacologically acceptable salt or hydrates thereof.

In the formula, R¹ represents hydrogen atom, a halogen atom or cyanogroup; R² and R¹ are the same as or different from and each representshydrogen atom, a C₁˜C₄ lower alkyl group or a halogen atom; R⁴represents hydrogen atom or a C₁˜C₄ lower alkyl group; and the ring Arepresents cyanophenyl group, aminosulfonylphenyl group, aminopyridylgroup, aminopyrimidyl group, halopyridyl group or cyanothiophenyl group,provided that the case where all of R¹, R² and R³ are hydrogen atoms,where both R² and R³ are hydrogen atoms, or where the ring A isaminosulfonyl group and both R¹ and R² are halogen atoms is excluded.Further, when the ring A is cyanophenyl group, 2-amino-5-pyridyl groupor a 2-halo-5-pyridyl group and R¹ is cyano group or a halogen atom, atleast one of R² and R³ should not be a hydrogen atom.

The present invention relates to a method for the prevention or therapyof the disease against which inhibitory of angiogenesis at the site oftumor, rheumatic arthritis or diabetic retinopathy is effective for theprevention or therapy, by administering a pharmacologically effectivedose of the above-mentioned indole compound, its pharmacologicallyacceptable salt or hydrates thereof to a patient.

The present invention further relates to a use of the above-mentionedindole compound, its pharmacologically acceptable salt or hydratesthereof for the manufacture of a preventive or therapeutic agent for thedisease against which an antiangiogenic agent is effective for theprevention or therapy.

The present invention furthermore relates to an antiangiogenic agent, anantitumor agent, a therapeutic agent for pancreatic cancer, atherapeutic agent for cancer of the colon, a therapeutic agent forgastric cancer, a therapeutic agent for breast cancer, a therapeuticagent for prostatic cancer, a therapeutic agent for lung cancer, atherapeutic agent for ovarian cancer, a cancer metastasis suppressor, atherapeutic agent for diabetic retinopathy, a therapeutic agent forrheumatic arthritis or a therapeutic agent for hematoma, which comprisesthe above-mentioned indole compound, its pharmacologically acceptablesalt or hydrates thereof as an effective ingredient. It relates to amethod for prevention, therapy and improvement by use of any of thosepharmaceutical agents. Further, it relates to a use of the abovecompound for the manufacture of any of those pharmaceutical agents.

In the above formula (I), a halogen atom means fluorine atom, chlorineatom, bromine atom or iodine atom. A C₁˜C₄ lower alkyl group means alinear or branched alkyl group such as methyl group, ethyl group,n-propyl group, n-butyl group, iso-propyl group, iso-butyl group andtert-butyl group.

The indole compound represented by the above formula (I) may form a saltwith an acid or with a base. The present invention also includes a saltof the indole compound (I) as well. Examples of the salt with an acidare an inorganic acid salt such as hydrochloride, hydrobromide orsulfate and that with an organic acid such as acetic acid, lactic acid,succinic acid, fumaric acid, maleic acid, citric acid, benzoic acid,methanesulfonic acid or p-toluenesulfonic acid. Examples of the saltwith a base are an inorganic salt such as sodium salt, potassium salt orcalcium salt and that with an organic base such as triethylamine,arginine or lysine.

It goes without saying that all hydrates of such a compound and of itspharmacologically acceptable salt are included. Although the compoundsof the present invention show a strong antiangiogenic effect, compoundswhich are subjected to metabolism such as oxidation, reduction,hydrolysis and conjugation in vivo are also included. The presentinvention further includes the compounds which produce the compound ofthe present invention as a result of metabolism such as oxidation,reduction and hydrolysis in vivo.

The compound of the present invention (I) can be manufactured by variousmethods and representative ones among them will be as follows.

It can be manufactured by the reaction of a sulfonic acid represented bythe formula (II):

(in the formula, the ring Aa represents cyanophenyl group,aminosulfonylphenyl group, aminopyridyl group, aminopyrimidyl group, ahalopyridyl group or cyanothiophenyl group) or a reactive derivativethereof with a compound represented by the formula (III):

(in the formula, R^(1a) represents hydrogen atom, a halogen atom orcyano group; and R^(2a) and R^(3a) are the same as or different from andeach represents hydrogen atom, a C₁˜C₄ lower alkyl group or a halogenatom, provided that the case where all of R^(1a), R^(2a) and R^(3a) arehydrogen atoms or where both R^(2a) and R^(3a) are hydrogen atoms isexcluded).

Examples of the reactive derivative of the sulfonic acid (II) arecommonly and well utilized reactive derivatives such as sulfonyl halide,sulfonyl acid anhydride and N-sulfonylimidazolide and the particularlyadvantageous example is a sulfonyl halide. Although there is noparticular limitation for the solvent used for the reaction, those whichdissolve the material substances and do not readily react with them arepreferred. For example, pyridine, tetrahydrofuran, dioxane, benzene,ethyl ether, dichloromethane, dimethylformamide and a mixed solventconsisting of two or more which are selected from them can be used. Inaddition, when an acid is liberated with a progress of the reaction asin the case of using a sulfonyl halide in the reaction, it is preferredto conduct the reaction in the presence of an appropriate deacidifyingagent and, therefore, the use of a basic solvent such as pyridine isparticularly appropriate. When a neutral solvent is used, a basicsubstance such as an alkali carbonate or an organic tertiary amine maybe added. of course, the solvent which can be used is not limited tothose listed here. Usually, the present reaction proceeds at roomtemperature but, if necessary, it may be cooled or heated. The reactiontime is usually from 10 minutes to 20 hours and is optionally selecteddepending upon the type of the material compounds and the reactiontemperature.

When an amino group is protected in the resulting product, aconventional deprotecting method such as treatment with an acid,treatment with an alkali and catalystic reduction may be carried outupon necessity whereby it is possible to give an indole compound (I)having a free amino group.

Now, methods for the manufacture of the starting compounds (II),reactive derivative thereof and (III) used in the present invention willbe illustrated.

The starting compound (II) and reactive derivative thereof include bothknown compounds and novel compounds. In the case of novel compounds,they can be manufactured by applying the already-reported syntheticmethod for known compounds or by combining them. For example, novelsulfonyl chloride may be manufactured by a method applying the syntheticmethods mentioned in Chem. Ber., 90, 841 (1957); J. Med. Chem., 6, 307(1963); J. Chem. Soc. (c), 1968, 1265; Chem. Lett., 1992, 1483; J. Am.Chem. Soc., 59, 1837 (1937); J. Med. Chem., 23, 1376 (1980); J. Am.Chem. Soc., 70, 375 (1948); J. Am. Chem. Soc., 78, 2171 (1956) etc.

When R^(1a) and R^(3a) are hydrogen atoms and R^(2a) is a halogen atomin the starting compound (III), it can be manufactured by a knownsynthetic method. When R^(2a) and R^(3a) are the same as or differentfrom and each represents hydrogen atom, a C₁˜C₄ lower alkyl group or ahalogen atom (the case where both are hydrogen atoms is excluded) andR^(1a) is cyano group, it can be manufactured as follows.

Reaction Formulae 1

In the formulae, R^(1a), R^(2a) and R^(3a) have the same meanings asdefined above.

Reaction Formulae 2

In the formulae, R^(1a), R^(2a) and R^(3a) have the same meanings asdefined before; and DPPA means diphenyl phosphoryl azide.

When R^(1a) is a halogen atom, it can be manufactured in such a mannerthat the formula (a) or the formula (g) in the above-mentioned reactionformulae (1) and (2) is halogenated by a conventional means and thenitro group is reduced or a protecting group of an amino group iseliminated.

When the compound of the present invention is used as a medicament, itis administered either orally or parenterally. The dose varies dependingupon degree of the symptom, age, sex, body weight and sensitivitydifference of the patient, method of the administration, period for theadministration, interval of the administration, property of thepharmaceutical preparation, type of the preparation, type of theeffective ingredients etc., and is not particularly limited. In the caseof intravenous administration, it is 1-2000 mg, preferably 1-1500 mgand, more preferably, 5-1000 mg while, in the case of oraladministration, it is usually 10-6000 mg, preferably about 50-4000 mgand, more preferably, 100-3000 mg per day for adults, and that isusually administered once daily or by dividing into up to three times aday.

When a solid preparation for oral administration is prepared, fillerand, if necessary, binder, disintegrating agent, lubricant, coloringagent, corrigent, etc. are added to the main ingredient, followed bysubjecting to a common method to make into tablets, coated tablets,granules, fine granules, powders, capsules etc.

Examples of the filler are lactose, corn starch, sucrose, glucose,sorbitol, crystalline cellulose and silicon dioxide; examples of thebinder are polyvinyl alcohol, ethyl cellulose, methyl cellulose, gumarabic, hydroxypropyl cellulose and hydroxypropyl methyl cellulose;examples of the lubricant are magnesium stearate, talc and silica;examples of the coloring agent are those which are allowed to add to thepharmaceuticals; and examples of the flavoring agents are cacao powder,menthol, aromatic, peppermint oil, borneol, and cinnamon powder. It isof course no problem that such tablets and granules are appropriatelycoated with a sugar coat, gelatin coat or others if necessary.

In preparing the injection, a pH adjusting agent, a buffer, a suspendingagent, a solubilizer, a stabilizer, an isotonizing agent, apreservative, etc. are added, if necessary, to the main ingredientfollowed by subjecting to a conventional method to make into injectionsfor intravenous, subcutaneous or intramuscular administration. At thattime, it may be made into a freeze-dried product by a common method ifnecessary.

Examples of the suspending agent are methyl cellulose, polysorbate 80,hydroxyethyl cellulose, gum arabic, tragacanth powder, sodiumcarboxymethyl cellulose and polyoxyethylene sorbitan monolaurate.

Examples of the solubilizer are polyoxyethylene hydrogenated castor oil,polysorbate 80, nicotinamide, polyoxyethylene sorbitan monolaurate,macrogol and castor oil fatty acid ethyl ester.

Examples of the stabilizer are sodium sulfite and sodium metasulfite.Examples of the preservative are methyl para-hydroxybenzoate, ethylpara-hydroxybenzoate, sorbic acid, phenol, cresol and chlorocresol.

Effect of the compounds of the present invention will be shown by way ofthe following pharmacological experimental examples.

Pharmacological Experimental Example 1

Antiangiogenic Effect

The inhibition degree of angiogenesis which was observed when aortapieces of rat were incubated in collagen was defined as anantiangiogenic effect. That is, the aorta excised from male rat ofSprague-Dawley strain (10-12 weeks age) was washed with a Hanks'solution so that fat tissues around there were removed minutely. Theaorta was incised to prepare pieces of 2 mm square and they were allowedto stand in a 24-well plate holding the endothelial cells upside. Then,500 μl of neutralized Type I collagen (Cell Matrix Type I-A;manufactured by Nitta Gelatin) were poured over each well and allowed tostand at room temperature for about 20 minutes in a clean bench tosolidify the gel. After confirming that the gel was solidified, 500 μlof MCDB 131 medium (manufactured by Chlorella Kogyo) were added theretofollowed by incubating in a CO₂ incubator (5% CO₂) at 37° C. On the nextday, the culture medium was exchanged with 500 μl of MCDB 131 mediumcontaining the test compound and the incubation was continued. Afterthree days, the medium was again exchanged with 500 μl of MCDB 131medium containing the test compound and, at the stage of the 7th dayfrom the initiation of addition of the test compound, numbers ofcapillaries formed around the aorta were counted under a microscope. Thesolution containing the test compound was prepared in a three-folddilution system where 10 μg/ml was the highest concentration.

Inhibiting rate was calculated from the following formula and 50%inhibiting concentration (IC₅₀) for each test compound was determined.

Inhibiting Rate (%)=(C−T)/C×100

C: Numbers of capillaries when no compound was added

T: Numbers of capillaries when a compound was added

TABLE 1 Test Compound IC₅₀ Value (Ex. No.) (μg/ml) Example 1 0.08Example 2 0.07 Example 3 0.10 Example 4 0.10 Example 5 0.15 Example 60.06 Example 7 0.42 Example 8 0.05 Example 9 0.05 Example 10 0.06

Pharmacological Experimental Example 2

Inhibitory Effect of Growth of Endothelial Cells

Endothelial cells derived from human umbilical vein (HUVEC; manufacturedby Sanko Junyaku) incubated in an EGM medium (manufactured by SankoJunyaku) containing 100 Units of penicillin and 100 μg/ml ofstreptomycin were adjusted to 0.8−1×10⁴ cells/ml and each 100 μl wereseparately placed on a 96-well plate. After incubating in a CO₂incubator (5% CO₂) at 37° C. overnight, 100 μl of EGM medium containingtest compound diluted in a three-fold manner were added thereto followedby incubating for three days. The cell numbers at that time weremeasured by MTT method. That is, 50 μl of phosphate buffer containing0.33% of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT) was added thereto and incubation was continued for 3-4 hours.Then, after the supernatant liquid of the culture was removed, 100 μl ofdimethyl sulfoxide (DMSO) was added to dissolve a formazane which wasformed in the cells and the absorbance at the wave length of 540 nm wasmeasured by use of plate reader (manufactured by Corona Denki).

Inhibiting rate was calculated from the following formula and 50%inhibiting concentration (IC₅₀) was determined for each compound.

Inhibition Rate (%)=(C−T)/C×100

C: Absorbance when no compound was added

T: Absorbance when a compound was added

TABLE 2 Test Compound IC₅₀ Value (Ex. No.) (μg/ml) Example 1 0.10Example 2 0.12 Example 3 0.62 Example 4 1.3 Example 5 0.98 Example 6 1.2Example 7 0.98 Example 8 0.49 Example 9 1.6 Example 10 0.38

Pharmacological Experimental Example 3

Inhibitory Effect of Proliferation of Mouse B16 Melanoma

Mouse B16 melanoma cells incubated in a Dulbecco-modified Eagle medium(DMED; manufactured by Nissui Seiyaku) containing 10% of fetal bovineserum, 100 Units/ml of penicillin and 100 μg/ml of streptomycin wereadjusted to 2×10⁴ cells/ml and each 100 μl thereof were separatelyplaced on a 96-well plate. After an incubation was carried out in a CO₂incubator (5% CO₂) at 37° C. for one night, then 100 μl of the aboveculture containing a test compound diluted in a 3-fold series were addedthereto followed by incubating for 3 days and the cell numbers at thattime were measured by an MTT method. Incidentally, a treatment with a0.33% MTT solution was carried out for 1-2 hour(s).

Inhibiting rate was calculated from the following formula and 50%inhibiting concentration (IC₅₀) was determined for each compound.

Inhibiting Rate (%)=(C−T)/C×100

C: Absorbance when no compound was added

T: Absorbance when a compound was added

TABLE 3 Test Compound IC₅₀ Value (Ex. No.) (μg/ml) Example 1 10 Example2 15 Example 3 21 Example 4 19 Example 5 8.8 Example 6 6.5 Example 7 7.5Example 8 19 Example 9 8.4 Example 10 23

It is apparent from Pharmacological Experimental Example 1 that thecompounds of the present invention exhibit a clear antiangiogeneiceffect. It is apparent from Pharmacological Experimental Examples 2 and3 that the proliferation inhibitory effect of the compounds of thepresent invention on B16 melanoma cells was 5 to 100-fold weaker thanthat on endothelial cells and accordingly that they specifically act theendothelial cells in blood vessel.

In the meanwhile, evaluation of an antitumor effect was carried out inaccordance with a method of Koyanagi, et al. (Cancer Res., 54,1702-1706, 1994) using a KP-1 cell strain derived from human pancreaticcancer and an HCT 116 cell strain derived from human cancer of thecolon. The above-mentioned human cancer cells (5×10⁶ cells) weresubcutaneously transplanted to nude mice (KSN) of 6 to 7 weeks age and,since the stage where it became to the size of about 100 mm³,administration of the compound of the present invention was started. Inthe experiments, ten mice were used for a group to which no drug wasadministered while, in a drug-administered group, five mice were usedfor each dose. The dose of 50 mg/kg, 100 mg/kg or 200 mg/kg wascontinuously administered per os two times a day and the size of thetumor on the 22nd day from the beginning of the administration wascompared with that in the group to which no drug was administered. Theresult was 37%, 30% and 11%, respectively in the KP-1 cell strainderived from human pancreatic cancer and 0.2%, 0.3% and 0.0%,respectively in the HCT 116 cell strain derived from human cancer of thecolon in the case of a group to which the compound of Example 1 wasadministered for example. Thus, the compound of Example 1 showed asignificant antitumor effect.

From the above results, the compound of the present invention can beexpected to exhibit an excellent effect in view of efficacy and safetyas compared with the known bactericidal antitumor agents which directlytarget cancer cells.

As noted in the above Experimental Examples, the compounds of thepresent invention have an excellent antiangiogenic effect and are usefulas antitumor agents for pancreatic cancer, cancer of the colon, gastriccancer, bread cancer, prostatic cancer, lung cancer and ovarian cancerand also as therapeutic agents for diabetic retinopathy, rheumaticarthritis and hematoma.

EXAMPLES

Hereinafter, Production Examples for showing the manufacture of thematerial compounds for the compounds of the present invention andExamples for showing the compounds of the present invention will beillustrated although it goes without saying that the present inventionis not limited thereto.

Production Example 1 Ethyl pyruvate N-(5-methyl-2-nitrophpnyl)hydrazone

To a mixed solution of 160 ml of water and 170 ml of concentratedhydrochloric acid was added 75.0 g (493 mmol) of 5-methyl-2-nitroanilinefollowed by stirring. An aqueous solution (80 ml) of 36.0 g (517 mmol)of sodium nitrite was added dropwise thereinto at −20° C. The reactionsolution was added to a solution which was prepared by dissolving ethyl2-methylacetacetate in 100 ml of ethanol followed by adding 200 ml of a12N aqueous solution of potassium hydroxide, at −20° C. with stirringduring 30 minutes. After the mixture was stirred at the same temperaturefor 30 minutes, 100 ml of concentrated hydrochloric acid were added andthe resulting precipitates were collected by filtration, washed withwater and dried in vacuo for overnight. A mixed solution of diethylether and hexane was added thereto, and the resulting crystals werecollected by filtration to give 130 g of the title compound.

¹H-NMR (DMSO-d₆) δ (ppm); 1.29(3H, t, J=7.2 Hz), 2.16(3H, s), 2.40(3H,s), 4.25(2H, q, J=7.2 Hz), 6.91(1H, dd, J=8.8, 2.0 Hz), 7.63(1H, s),8.07(1H, d, J=8.8 Hz), 10.69(1H, s).

Production Example 2 Ethyl 4-methyl-7-nitro-1H-indole-2-carboxylate

To 250 ml of a suspension of 25.0 g (94.2 mmol) of the compound ofProduction Example 1 in xylene was added 100 g of polyphosphoric acidfollowed by heating under reflux for 3 hours. To the reaction solutionwere added 80 ml of water and 300 ml of ethyl acetate under ice-cooling.The resulting insoluble matters were filtered off followed by washingwith 1.5 liters of ethyl acetate, and the resulting filtrate wasextracted with ethyl acetate. The organic layer was successively washedwith a saturated sodium bicarbonate solution, water and brine, driedover magnesium sulfate and concentrated to dryness. To the resultingresidue was added a mixed solution of tert-butyl methyl ether andhexane, and the resulting crystals were collected by filtration to give11.1 g of the title compound.

¹H-NMR (DMSO-d₆) δ (ppm); 1.35(3H, t, J=7.2 Hz), 2.65(3H, s), 4.38(2H,q, J=7.2 Hz), 7.16(1H, d, J=8.4 Hz), 7.51(1H, s), 8.19(1H, d, J=8.4 Hz),11.29(1H, br s).

Production Example 3 4-Methyl-7-nitron-1H-indole-2-carboxylic Acid

To 150 ml of a solution of 11.0 g (44.3 mmol) of the compound ofProduction Example 2 in tetrahydrofuran was added 150 ml of a 1N aqueoussolution of sodium hydroxide followed by heating under stirring at 80°C. for 30 minutes. The reaction solution was concentrated, 40 ml of 5Nhydrochloric acid was added to the resulting residue under ice-coolingto adjust to pH 1, and the resulting precipitates were filtered andwashed with water. The precipitates were dissolved in 300 ml oftetrahydrofuran and extracted with ethyl acetate. The organic layer waswashed with brine, dried over magnesium sulfate and concentrated todryness to give 9.60 g of the title compound.

¹H-NMR (DMSO-d₆) δ (ppm); 2.62(3H, s), 7.13(1H, d, J=8.0 Hz), 7.42(1H,S), 8.15(1H, d, J=8.0 Hz), 11.00(1H, brs).

Prduction Example 4 4-Methyl-7-nitro-1H-indole

Into 60 ml of 1,3-dimethyl-2-imidazolidinone was dissolved 9.58 g (43.5mmol) of the compound of Production Example 3, 1.04 g (4.35mmol) ofbasic copper carbonate was added thereto and the mixture was heatedunder stirring at 180° C. for 4 hours. To the reaction solution wasadded 120 ml of ethyl acetate under ice-cooling, the resulting insolublematters were filtered off and the resulting filtrate was extracted withethyl acetate. The organic layer was washed with water and brinesuccessively and dried over magnesium sulfate. After the concentration,the resulting residue was purified by a silica gel column chromatographyto give 4.87 g of the title compound.

¹H-NMR (DMSO-d₆) δ (ppm); 2.59(3H, s), 6.74(1H, s), 7.03(1H, d, J=8.4Hz), 7.48(1H, s), 8.00(1H, d, J=8.4 Hz), 11.86(1H, brs).

Production Example 5 3-Formyl-4-methyl-7-nitro-1H-indole

To 12 ml (154 mmol) of dimethylformamide was added 1.5 ml (16.1 mmol) ofphosphorus oxychloride at 0° C. in a nitrogen atmosphere followed bystirring at room temperature at the same temperature for 20.5 hours. Asolution (20 ml) of 2.0 g (11.4 mmol) of the compound of ProductionExample 4 in dimethylformamide was added thereto at 0° C. followed byheating at 90° C. for 21 hours under stirring. To the reaction solutionwas added 100 ml of a 1N aqueous solution of sodium hydroxide underice-cooling followed by extracting with ethyl acetate. The organic layerwas washed with water and brine successively, dried over magnesiumsulfate and concentrated to dryness. To the resulting residue was addeda mixed solution of tert-butyl methyl ether and hexane and the resultingcrystals were collected by filtration to give 2.23 g of the titlecompound.

¹H-NMR (DMSO-d₆) δ (ppm); 2.90(3H, s), 7.21(1H, d, J=8.4 Hz), 8.11(1H,d, J=8.4 Hz), 8.39(1H, s), 10.01(1H, s), 12.71(1H, brs).

Production Example 6 3-Cyano-4-methyl-7-nitron-1H-indole Into 100 ml ofdimethylformamide was dissolved 2.21 g

(10.8 mmol) of the compound of Production Example 5 followed by adding900 mg (13.0 mmol) of hydroxylamine hydrochloride and 1.05 ml (13.0mmol) of pyridine thereto. After heating at 60° C. under stirring for 40minutes, 53.9 mmol of 1,1′-carbonyldiimidazole (53.9 mmol) were added tothe reaction solution under ice-cooling. After heating at 60° C. forfurther 30 minutes under stirring, 3.0 ml (21.5 mmol) of triethylaminewas added to the reaction solution followed by heating at the sametemperature for further 1 hour under stirring. To the reaction mixturewas added 50 ml of ice water under ice-cooling followed by extractingwith ethyl acetate. The organic layer was washed with water and brinesuccessively, dried over magnesium sulfate and concentrated to dryness.To the resulting residue was added a mixed solution of tert-butyl methylether and hexane, and the resulting crystals were collected byfiltration to give 1.95 g of the title compound.

¹H-NMR (DMSO-d₆) δ (ppm); 2.78(3H, s), 7.22(1H, d, J=8.0 Hz), 8.14(1H,d, J=8.0 Hz), 8.41(1H, s), 12.76(1H, brs).

Production Example 7 7-Bromo-4-methyl-1H-indole

To 300 ml of a solution of 65.0 g (301 mmol) of2-bromo-5-methylnitrobenzene in tetrahydrofuran was added 1 liter of a1.0M solution of vinyl magnesium bromide (1 mol) in tetrahydrofuran at−60° C. in a nitrogen atmosphere under stirring during 1 hour. To thereaction mixed solution were added a saturated aqueous solution ofammonium chloride and ethyl acetate, and the resulting insoluble matterswere filtered off. The resulting filtrate was dried over magnesiumsulfate, concentrated, and then the resulting residue was purified by asilica gel column chromatography to give 35.5 g of the title compound.

¹H-NMR (DMSO-d₆) δ (ppm); 2.42(3H, s), 6.55(1H, s), 6.73(1H, d, J=7.6Hz), 7.16(1H, d, J=7.6 Hz), 7.35(1H, s), 11.24(1H, brs).

Production Example 8 4-Methyl-1H-indole-7-carboxylic Acid

To a solution (200 ml) of 35.5 g (169 mmol) of the compound ofProduction Example 7 in tetrahydrofuran was added a 1.6M solution (350ml) of butyl lithium (384 mmol) in hexane in a nitrogen atmosphere at−78° C. under stirring. After stirring for 40 minutes under ice-cooling,carbon dioxide was introduced to the reaction solution at −50° C. andstirred as it was for 15 minutes. Water was added to the reactionmixture at the same temperature, the solvent was evaporated and theresulting precipitates were collected by filtration and washed withwater. The precipitates were dissolved in 300 ml of tetrahydrofuran,dried over magnesium sulfate and then concentrated to dryness to give25.9 g of the title compound.

¹H-NMR (DMSO-d₆) δ (ppm); 2.51(3H, s), 6.53(1H, s), 6.88(1H, d, J=7.6Hz), 7.31(1H, s), 7.62(1H, d, J=7.6 Hz), 10.99(1H, brs), 12.79(1H, brs).

Production Example 9 7-(N-tert-Butoxcarbonyl)amino-4-methyl-1H-indole

In 80 ml of toluene was suspended 7.0 g (40.0 mmol) of the compound ofProduction Example 8, then 22 ml (160 mmol) of triethylamine and 11.2 ml(52 mmol) of diphenylphosphoryl azide were added thereto in a nitrogenatmosphere and the mixture was stirred at room temperature for 30minutes. To the reaction solution was added 8 ml (84 mmol) oftert-butanol, the mixture was heated under stirring at 100° C. for 2.5hours and then the reaction solution was concentrated. The resultingresidue was dissolved in ethyl acetate, washed with 0.1N hydrochloricacid, water and brine successively, dried over magnesium sulfate andconcentrated to dryness. To the resulting residue was added a mixedsolution of diethyl ether and hexane, and the resulting crystals werecollected by filtration to give 7.87 g of the title compound.

¹H-NMR (DMSO-d₆) δ (ppm); 1.48(9H, s), 2.38(3H, s), 6.37-6.44(1H, m),6.68(1H, d, J=8.4 Hz), 7.22-7.31(2H, m), 8.86(1H, brs), 10.73(1H, brs).

Production Example 107-(N-tert-Butoxycarbonyl)amino-3-formyl-4-methyl-1H-indole

To 400 ml (5.2 mol) of dimethylformamide was added 40 ml (429 mmol) ofphosphorous oxychloride at 0° C. in a nitrogen atmosphere followed bystirring at the same temperature for 25 min. At 0° C., 74.0 g (300 mmol)of the compound of Production Example 9 was added thereto followed bystirring at room temperature for 1.5 hr. To the reaction mixture wasadded 250 ml of a 5N aqueous solution of sodium hydroxide underice-cooling to adjust to pH8. Tetrahydrofuran, ethyl acetate and waterwere added thereto to separate the organic layer, followed by washingwith water and brine successively. After drying over magnesium sulfate,the solvent was evaporated. To the resulting residue was added a mixedsolution of diethyl ether and hexane, and the resulting crystals werecollected by filtration to give 53.7 g of the title compound.

¹H-NMR (DMSO-d₆) δ (ppm); 1.50(9H, s), 2.71(3H, s), 6.90(1H, d, J=7.6Hz), 7.32-7.41(1H, m), 8.21(1H, d, J=1.6 Hz), 8.99(1H, brs), 9.93(1H,s), 11.88(1H, brs).

Production Example 117-(N-tert-Butoxycarbonyl)amino-3-cyano-4-methyl-1H-indole

In 50 ml of dimethylformamide was dissolved 4.43 g (16.2 mmol) of thecompound of Production Example 10 followed by adding 1.35 g (19.4 mmol)of hydroxylamine hydrochloride and 1.6 ml (19.8 mmol) of pyridinethereto. After heating under stirring at 60° C. for 45 min,1,1′-carboyldiimidazole (80.8mmol) was added to the reaction solutionunder ice-cooling. After heating under stirring at 60° C. for further 30min, 4.5 ml (32.3 mmol) of triethyl amine was added to the reactionsolution followed by heating under stirring at the same temperature forfurther 30 min. Water was added to the reaction mixture underice-cooling followed by extracting with ethyl acetate. The organic layerwas washed with water and brine successively, dried over magnesiumsulfate and then concentrated to give 4.27 g of the title compound.

¹H-NMR (DMSO-d₆) δ (ppm); 1.49 (9H, s), 2.60(3H, s), 6.89(1H, d, J=8.0Hz), 7.34-7.42(1H, m), 8.20(1H, d, J=2.8 Hz), 9.04(1H, brs), 11.80(1H,brs).

Production Example 12 7-Amino-3-cyan)-4-methyl-1H-indole

Into a mixed solution of 100 ml of tetrahydrofuran and 100 ml ofmethanol were suspended 12.6 g (62.6 mmol) of the compound of ProductionExample 6, and hydrogenation was carried out at 3 atmospheric pressureand at ambient temperature in the presence of 430 mg (1.87 mmol) ofplatinum oxide. The filtrate was filtered off followed by concentratingto dryness, a mixed solution of tert-butyl methyl ether and hexane wasadded to the residue and the crystals were collected by filtration togive 10.7 g of the title compound. Into 400 ml of dichloromethane wasdissolved 50.5 g (186 mmol) of the compound of Production Example 11 and210 ml (2.76 mmol) of trifluoroacetic acid was added thereto at 0° C. ina nitrogen atmosphere followed by stirring at room temperature for 40minutes. To the reaction solution was added a 5N aqueous solution ofsodium hydroxide at −20° C. to adjust to pH 7. The solvent was removedand the residue was extracted with ethyl acetate. The organic layer waswashed with water and brine successively, dried over magnesium sulfateand concentrated to dryness. A mixed solution of diethyl ether andhexane was added to the resulting residue and the crystals werecollected by filtration to give 24.5 g of the title compound.

¹H-NMR (DMSO-d₆) δ (ppm); 2.47(3H, s), 5.07(2H, s), 6.34(1H, d, J=7.6Hz), 6.64(1H, d, J=7.6 Hz), 8.10(1H, s), 11.70(1H, brs).

Production Example 13 3-(Cyanobenzenesulfonyl Chloride

To a mixed solution of 200 ml of water and 250 ml of concentratedhydrochloric acid was added 25.0 g (212 mmol) of 3-cyanoaniline followedby stirring. An aqueous solution (80 ml) of 15.5 g (223 mmol) of sodiumnitrite was added dropwise thereinto at −10° C. The reaction solutionwas added to acetic acid saturated with sulfur dioxide (prepared bysaturating sulfur dioxide in 250 ml of acetic acid followed by adding2.1 g of cuprous chloride) under ice-cooling and stirring. After 1 hour,the reaction solution was poured onto 500 ml of ice water and extractedwith diethyl ether. The extract was washed with a saturated aqueoussolution of sodium bicarbonate, water and brine successively, and driedover magnesium sulfate. The solvent was evaporated, a mixed solution ofdiethyl ether and hexane was added to the residue and the crystals werecollected by filtration to give 16.0 g of the title compound.

¹H-NMR (DMSO-d₆) δ (ppm); 7.55(1H, t, J=8.0 Hz), 7.78(1H, dd, J=8.0, 1.2Hz), 7.86-7.92(2H,m).

Production Example 14 4-Sulfamoylbenzenesulfonyl Chloride

To a mixed solution of 80 ml water and 50 ml of concentratedhydrochloric acid was added 25.0 g (145 mmol) of4-aminobenzenesulfonamide followed by stirring. An aqueous solution (20ml) of 10.5 g (152 mmol) of sodium nitrite was added dropwise thereintoat −13° C. to −10° C. during 15 min. After 10 min, the reaction solutionwas added to a mixed solution saturated with sulfur dioxide (prepared bysaturating sulfur dioxide in a mixed solution of 150 ml of acetic acidand 12.5 ml of concentrated hydrochloric acid followed by adding 3. 7 gof cuprous chloride) at −30° C. under stirring. After 1 hr, 500 ml ofice water was added to the reaction solution, and the resultingprecipitates were collected by filtration. The precipitates weredissolved in a mixed solution of 450 ml of toluene and 150 ml of ethylacetate. After the resulting insoluble matters were filtered off, thefiltrate was extracted with ethyl acetate. The organic layer was washedwith a saturated sodium bicarbonate solution and brine successively, anddried over magnesium sulfate. The solvent was evaporated, 100 ml oftoluene was added to the resulting residue and the crystals werecollected by filtration to give20.9 g of the title compound.

¹H-NMR (DMSO-d₆) δ (ppm); 7.65-7.69(2H,m), 7.71-7.78(4H,m).

Production Example 15 5-Bromo-3-chloro-7-nitro-1H-indole

To a solution of 12.00 g (49.8 mmol) of 5-bromo-7-nitro-1H-indole in 140ml of tetrahydrofuran were added 1.4 ml of dimethylformamide and 6.98 g(52.3 mmol) of N-chlorosuccinimide followed by stirring at roomtemperature overnight. A 10% aqueous solution of sodium thiosulfate wasadded thereto followed by extracting with ethyl acetate. The organiclayer was washed with water and brine successively, dried over magnesiumsulfate and concentrated to dryness to give 14.84 g of the titlecompound.

¹H-NMR (DMSO-d₆) δ (ppm); 7.79(1H, s), 8.15(1H, s), 8.23(1H, s),12.32(1H, brs).

Production Example 16 7-Amino-5-bromo-3-chloro-1H-indole Hydrochloride

To a solution (250 ml) of 14.84 g (53.9 mmol) of the compound ofProduction Example 15 in methanol were added 70 ml of concentratedhydrochloric acid and 31.97 g (269 mmol) of tin dust, followed bystirring at room temperature for 80 minutes. After a 5N aqueous solutionof sodium hydroxide was added thereto under ice-cooling to adjust to pH10, the resulting precipitates were filtered off and the filtrate wasextracted with ethyl acetate. The organic layer was washed with asaturated sodium bicarbonate solution and brine successively, dried overmagnesium sulfate and concentrated. Then, the resulting residue waspurified by silica gel column chromatography to give 14.35 g of7-amino-5-bromo-3-chloro-1H-indole. It was dissolved in ethyl acetateand a mixed solution (17 ml) of 4N hydrogen chloride and ethyl acetatewas added thereto. The resulting precipitates were collected byfiltration and washed with hexane to give 13.23 g of the title compound.

¹H-NMR (DMSO-d₆) δ (ppm); 5.11(3H, brs), 6.64(1H, s), 6.93(1H, s),7.50(1H, d, J=2.0 Hz), 11.38(1H, brs).

Production Example 17 Ethyl pyruvate 2-(4-methyl-2-nitrophenyl)hydrazone

Into 110 ml of water was suspended 30.00 g (0.197 mol) of4-methyl-2-nitroaniline followed by adding 66 ml of concentratedhydrochloric acid thereto. An aqueous solution (35 ml) of 16.33 g (0.237mol) of sodium nitrite was added dropwise thereinto at 10° C. or below,followed by stirring for 40 minutes under ice-cooling to prepare adiazonium salt solution. In a mixed solution of 150 ml of ethanol and300 ml of water was dissolved 28.43 g (0.197 mol) of ethyl2-methylacetoacetate, followed by adding 120 ml of an aqueous solutionof 53.36 g (0.808 mol) of potassium hydroxide thereto under ice-cooling.Then, the previously-prepared diazonium salt solution was added dropwisethereinto at the same temperature and stirred under ice-cooling for 20minutes. After concentrated hydrochloric acid was added thereto toadjust to pH 1, the resulting precipitates were collected by filtration,washed with water and vacuum dried on phosphorus pentaoxide to give46.42 g of the title compound.

¹H-NMR (DMSO-d₆) δ (ppm); 1.40(3H, t, J=7.2 Hz), 2.23(3H, s), 2.36(3H,s), 4.35(2H, q, J=7.2 Hz), 7.44(1H, dd, J=8.8, 1.6 Hz), 7.93(1H, d,J=8.8 Hz), 8.00(1H, s), 10.87(1H, brs).

Production Example 18 Ethyl 5-methyl-7-nitro-1H-indole-2-carboxylate

To a solution (320 ml) of 15.92 g (60.0 mmol) of the compound ofProduction Example 17 in xylene was added polyphosphoric acid followedby heating under stirring overnight. Water and ethyl acetate were addedthereto, the resulting insoluble matters were filtered off and theorganic layer was separated. The organic layer was washed with water andbrine successively, dried over magnesium sulfate and concentrated. Then,the resulting residue was purified by silica gel column chromatographyto give 7.32 g of the title compound.

¹H-NMR (DMSO-d₆) δ (ppm); 1.34(3H, t, J=7.0 Hz), 2.47(3H, s), 4.36 (2H,q, J=7.0 Hz), 7.35 (1H, s), 7.99 (1H, s), 8.11 (1H, s), 11.25 (1H, brs).

Production Example 19 5-Methyl-7-nitro-1H-indole

To a solution (80 ml) of 7.86 g (31.7 mmol) of the compound ofProduction Example 18 in tetrahydrofuran was added 150 ml of a 1Naqueous solution of sodium hydroxide under ice-cooling followed bystirring at room temperature for 3.5 hr. Under ice-cooling, 2Nhydrochloric acid was added thereto to adjust to pH1 followed byextracting with ethyl acetate. The organic layer was washed with waterand brine successively, dried over magnesium sulfate and thenconcentrated to dryness to give 7.13 g of5-methyl-7-nitro-1H-indole-2-carboxylic acid. The resulting compound wasdissolved in 160 ml of 1,3-dimethyl-2-imidazolidinone followed by adding716 mg (3.24 mmol) of basic copper carbonate and stirring at 185° C. for2 hr. The reaction solution was poured into water, the resultinginsoluble matters were filtered off, and the resulting filtrate wasextracted with ethyl acetate. The organic layer was washed with waterand brine successively, dried over magnesium sulfate and concentrated.Then, the resulting residue was purified by silica gel columnchromatography to give 4.50 g of the title compound.

¹H-NMR (DMSO-d₆) δ (ppm); 2.46(3H, s), 6.62(1H, d, J=2.8 Hz), 7.47(1H,d, J=2.8 Hz), 7.87(1H, s), 7.92(1H, s), 11.77(1H, brs).

Production Example 20 3-Bromo-5-methyl-7-nitron-1H-indole

To a solution (70 ml) of 4.50 g (25.5 mmol) of the compound ofProduction Example 19 in tetrahydrofuran were added 0.7 ml ofdimethylformamide and 4.78 g (26.9 mmol) of N-bromosuccinimide, followedby stirring at room temperature for 70 min. A 10% aqueous solution ofsodium thiosulfate was added thereto followed by extracting with ethylacetate. The organic was washed with water and brine successively, driedover magnesium sulfate and then concentrated to dryness to give 6.53 gof the title compound.

¹H-NMR (DMSO-d₆) δ (ppm); 2.50(3H, s), 7.67(1H, s), 7.73(1H, s),8.02(1H, s), 12.10(1H, brs).

Production Example 21 7-Amino-3-bromo-5-methyl-1H-indole

Into a mixed solution of 150 ml of methanol and 75 ml of water wassuspended 6.76 g (26.5 mmol) of the compound of Production Example 20,and then 11.34 g (212 mmol) of ammonium chloride and 5.92 g (106mmol) ofiron powder were added thereto. After stirring at 80° C. for 1 hour, theresulting insoluble matters were filtered off. A saturated sodiumbicarbonate solution was added to the filtrate to adjust to pH 8followed by extracting with ethyl acetate.

The organic layer was washed with a saturated sodium bicarbonatesolution, water and brine successively, dried over magnesium sulfate andconcentrated. Then, the resulting residue was purified by silica gelcolumn chromatography to give 3.30 g of the title compound.

¹H-NMR (DMSO-d₆), δ (ppm); 2.24(3H, s), 5.08(2H, brs), 6.20(1H, s),6.41(1H, s), 7.35(1H, s), 10.86(1H, brs).

Production Example 22 6-Amino-3-pyridinesulfonyl Chloride

To 123.8 g (1.06 mol) of chlorosulfonic acid was added 10.00 g (0.106mol) of 2-aminopyridine by portions under ice-cooling. Thionyl chloride(50.56 g, 0.425 mol) was added thereto, followed by heating under refluxfor 2.5 hours and further stirring at 150° C. for 7 hours. The reactionsolution was poured onto ice water, neutralized by adding sodiumbicarbonate thereto and extracted with ethyl acetate. The organic layerwas washed with a saturated sodium bicarbonate solution, water and brinesuccessively, dried over magnesium sulfate and then concentrated todryness. The resulting residue was suspended in ethyl ether and theinsoluble matters were filtered off. The filtrate was concentrated todryness and the resulting residue was recrystallized from ethylether-hexane to give 6.58 g of the title compound.

Production Example 23 4,7-Dibromo-1H-indole

From 62.0 g (0.224 mol) of 2,5-dibromonitrobenzene was obtained 27.2 gof the title compound by the same manner as in Production Example 1 ofJP-A 7-165708.

¹H-NMR (DMSO-d₆) δ (ppm); 6.52(1H, d, J=3.2 Hz), 7.18 (1H,d,J=8.0 Hz),7.26 (1H, d,J=8.0 Hz), 7.53 (1H, d, J=3.2 Hz), 11.75(1H, brs).

Production Example 24 7-Amino-4-bromo-1H-indole Hydrochloride

Into a solution (300 ml) of 27.2 g (98.9 mmol) of the compound ofProduction Example 23 in tetrahydrofuran was added dropwise 186 ml(116.3 mmol) of a 1.6M solution of n-butyl lithium in hexane in anitrogen atmosphere at −78° C. followed by stirring for 1 hour underice-cooling. After cooling again to −78° C., 28 ml (0.13 mmol) ofdiphenylphosphoryl azide was added dropwise thereinto and the mixturewas stirred at −78° C. for 1 hour and then at −40° C. for 1 hour. Afteradding 150 g of a 3.4M solution of sodium bis(2-methoxyethoxy)aluminumhydride in toluene thereto at −40° C., it was stirred at roomtemperature for 1 hour. Water (120 ml) was added thereto, the resultinginsoluble matters were collected by filtration and the filtrate wasextracted with ethyl ether. The organic layer was washed with asaturated sodium bicarbonate solution and brine successively, and driedover magnesium sulfate. After it was concentrated, the resulting residuewas dissolved in ethyl ether, 50 ml of a mixed solution of 4Nhydrochloric acid and ethyl acetate was added thereto, and the resultingprecipitates were collected by filtration to give 14.5 g of the titlecompound.

¹H-NMR (DMSO-d₆) δ (ppm); 6.41-6.43(1H, m), 6.80(1H,d,J=8.0 Hz),7.16(1H,d,J=8.0 Hz), 7.54(1H, t, J=2.8 Hz), 11.57(1H, brs).

Production Example 25 7-Bromo-4-chloro-1H-indole

The title compound was obtained by the same manner as in ProductionExample 23.

¹H-NMR (DMSO-d₆) δ (ppm); 6.60-6.61(1H, m), 7.04(1H, d, J=8.1 Hz),7.32(1H,d,J=8.1 Hz), 7.53(1H, t,J=2.7 Hz), 11.74(1H, brs).

Production Example 26 7-Amino-4-chloro-1H-indole Hydrochloride

The title compound was obtained by the same manner as in ProductionExample 24.

¹H-NMR (DMSO-d₆) δ (ppm); 6.54-6.55(1H, m), 7.05(1H, d, J=8.1 Hz),7.11(1H, d, J=8.1 Hz), 7.60(1H, t, J=2.7 Hz), 11.82(1H, brs).

Production Example 27 9-Bromo-2-thiophenecarhoxy Aldehyde

To a solution (80 ml) of 10.0 g (41.3 mmol) of 5-dibromothiophene intetrahydrofuran was added dropwise 27.0 ml (43.4 mmol) of a 1.6Msolution of n-butyllithium in hexane in a nitrogen atmosphere at −78°C., followed by stirring at the same temperature for 10 min. Then, 3.5ml (45.5 mmol) of dimethylformamide was added thereto at the sametemperature, followed by stirring for 20 min. Water was added thereto,followed by extracting with ethyl acetate. The organic layer was washedwith a 0.1N aqueous solution of hydrochloric acid, water and brinesuccessively, and dried over magnesium sulfate. It was concentrated todryness to give 6.4 g of the title compound.

¹H-NMR (DMSO-d₆) δ (ppm); 7.49(1H, d, J=4.0 Hz), 7.87(1H, d, J=3.9 Hz),9.81(1H, s).

Production Example 28 9-Bromo-2-thiophene Carbonitrile

To a solution of 8.2 g (43.1 mmol) of the compound of Production Example27 in 40 ml of dimethylformamide were added 3.3 g (51.7 mmol) ofhydroxylamine hydrochloride and 4.1 g (51.7 mmol) of pyridine followedby stirring at room temperature for 30 minutes. Then, 34.9 g (215.5mmol) of 1,1′-carbonyldiimidazole were added thereto under ice-coolingfollowed by stirring at room temperature for 1 hour. Ice water was addedto the reaction solution followed by extracting with ethyl acetate. Theorganic layer was washed with a 0.1N aqueous solution of hydrochloricacid, water and brine successively, and dried over magnesium sulfate.After it was concentrated, the resulting residue was purified by asilica gel column chromatography to give 6.7 g of the title compound.

¹H-NMR (DMSO-d₆) δ (ppm); 7.45(1H, d, J=4.0 Hz), 7.84(1H, d, J=4.0 Hz).

Production Example 29 5-Benzylthio-2-thiophene Carbonitrile

Into 10 ml of dimethyl sulfoxide was suspended 585 mg (13.4 mmol; 55%oily) of sodium hydride, and then 1.4 g (11.2 mmol) of benzylmercaptanwas added thereto under ice-cooling, followed by stirring for 10minutes. Then 2.1 g (11.2 mmol) of the compound of Production Example 14were added thereto followed by stirring at room temperature for 1 hour.Water was added to the reaction solution followed by extracting withethyl acetate. The organic layer was washed with water and brinesuccessively and dried over magnesium sulfate. After it wasconcentrated, the resulting residue was purified by silica gel columnchromatography to give 1.51 g of the title compound.

¹H-NMR (DMSO-d₆) δ (ppm); 4.26(2H, s), 7.18(1H, d, J=4.0 Hz),7.27-7.30(5H,m), 7.83(1H,d,J=4.0 Hz).

Production Example 30 4-Bromo-1H-indole Carboxylic Acid

From 51 g of the compound of Production Example 23 was obtained 34 g ofthe title compound by the same manner as in Production Example 8.

¹H-NMR (CDCl₃) δ (ppm); 6.51-6.52(1H, m), 7.35(1H, d, J=8.0 Hz),7.48(1H, t, J=2.8 Hz), 7.66(1H, d, J=8 Hz), 11.4(1H, brs), 13.2 (1H,brs).

Production Example 31 7-(N-tert -Butoxycarbonyl)amino-4-bromo-1H-indole

From 34 g of the compound of Production Example 30 was obtained 32 g ofthe title compound by the same manner as in Production Example 9.

¹H-NMR (CDCl₃) δ (ppm); 1.51(9H, s), 6.38-6.39(1H,m), 7.13(1H, d, J=8.0Hz), 7.44-7.46(2H, m), 9.11(1H, brs), 11.2(1H, brs).

Production Example 32 7-tert-Butoxycarbonyl)amine-4-bromo-3-1H-indole

The title compound was obtained by treating with N-chlorosuccinimide ina solution of the compound of Production Example 31 intetrahydrofuran/dimethylformamide.

¹H-NMR (CDCl₃) δ (ppm); 1.50(9H, s), 7.19(1H,d,J=8.4 Hz),7.45(1H,d,J=8.4 Hz), 7.62(1H,d,J=2.8 Hz), 9.08(1H, brs), 11.41(1H, brs).

Production Example 33 7-Amino-4-bromo-3-chloro-1H-indole Hydrochloride

The compound (10.87 g, 31.5 mmol) of Production Example 32 was dissolvedin 120 ml of methanol, and 20 ml of concentrated hydrochloric acid wasadded thereto followed by stirring at 60° C. for 40 minutes. Aftercompletion of the reaction, the solvent was removed and the resultingresidue was subjected to an azeotropic distillation for three times withethanol. The resulting residue was washed with ether to give 8.5 g ofthe title compound.

¹H-NMR (CDCl₃) δ (ppm); 6.67 (1H,d,J=8.0 Hz), 7.13 (1H, d, J=8.0 Hz),7.65(1H,d,J=2.8 Hz), 11.74(1H, brs).

Production Example 34 2-Amino-5-pyrimidine Sulfonyl Chloride

In ice-water, 21 ml (0.316 mol) of chlorosulfonic acid was cooled and 3g (0.032 mol) was added thereto by portions under stirring. Further, 9.2ml (0.126 mol) of thionyl chloride was added thereto followed bystirring at 150° C. for 70 hours. The reaction solution was returned toroom temperature and poured on water and the mixture was extracted withethyl acetate. The extract was dried over sodium sulfate andconcentrated to dryness to give 1.7 g of the title compound.

¹H-NMR (CDCl₃) δ (ppm); 5.97(2H, broad), 8.83(2H, s).

EXAMPLE 1 3-Cyano-N-(3-cyano-4-methyl-1H-indol-7-yl)benzenesulfonamide

The compound (2.00 g, 11.7 mmol) of Production Example 12 was dissolvedin 60 ml of tetrahydrofuran, and then 4.0 ml (49.5 mmol) of pyridine and2.60 g (12.9 mmol) of the compound of Production Example 13 were addedthereto. After stirring at room temperature for 16 hr, a 2N hydrochloricacid was added thereto to adjust to pH 1-2, and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand brine successively, dried over magnesium sulfate and concentrated.Then, the resulting residue was purified by silica gel columnchromatography to give 3.90 g of the title compound.

m.p.: 220-221° C. (recrystallized from ethanol/n-hexane)

¹H-NMR (DMSO-d₆) δ (ppm); 2.55(3H,s), 6.50(1H,d,J=8.0 Hz),6.77(1H,d,J=8.0 Hz), 7.71(1H, t, J=8.0 Hz), 7.90(1H, d, J=8.0 Hz),8.05-8.13(2H, m), 8.16(1H, s), 10.11(1H, brs), 12.01(1H, brs).

EXAMPLE 26-Chloro-N-(3-cyano-4-methyl-1H-indole-7-yl)-3-pyridinesulfonamide

The compound (700 mg, 4.09 mmol) of Production Example 12 was dissolvedin 20 ml of tetrahydrofuran, and then 1.3 ml (16.1 mmol) of pyridine and950 mg(4.48 mmol) of 6-chloro-3-pyridinesulfonylchloride were addedthereto. After stirring at room temperature for 2 hours, a 1Nhydrochloric acid was added thereto to adjust to pH 1-2 and the mixturewas extracted with ethyl acetate. The organic layer was washed withwater and brine successively, dried over magnesium sulfate andconcentrated. Then, the resulting residue was purified by silica gelcolumn chromatography to give 1.16 g of the title compound.

m.p.: 262-2630° C. (recrystallized from ethanol/hexane)

¹H-NMR (DMSO-d₆) δ (ppm); 2.57(3H, s), 6.55(1H,d,J=7.6 Hz),6.82(1H,d,J=7.6 Hz), 7.69(1H,d,J=8.4 Hz), 8.01(1H, dd, J=8.4,2.4 Hz),8.17(1H, d, J=2.8 Hz), 8.60(1H, d, J=2.4 Hz), 10.21(1H, brs), 12.03(1H,brs).

EXAMPLE 3N-(3-Bromo-5-methyl-1H-indole-7-yl)-4-sulfamoylbenzenesulfonamide

The compound (200 mg, 0.89 mmol) of Production Example 22 was dissolvedin 6 ml of tetrahydrofuran, and then 0.3 ml (3.71 mmol) of pyridine and300 mg (1.17 mmol) of the compound of Production Example 14 were addedthereto. After stirring at room temperature for 48 hr, a 1N hydrochloricacid was added thereto to adjust pH to 1-2 and the mixture was extractedwith ethyl acetate. The organic layer was washed with water and brinesuccessively, dried over magnesium sulfate and concentrated. Then, amixed solution of diethyl ether and hexane was added to the resultingresidue and crystals were collected by filtration to give 387 mg of thetitle compound.

m.p.: 196-197° C. (recrystallized from ethanol/n-hexane)

¹H-NMR (DMSO-d₆) δ (ppm); 2.24(3H,s), 6.60(1H,s), 6.98(1H, s),7.44(1H,s), 7.55(2H, brs), 7.85-7.95(4H,m), 10.13(1H, brs), 11.01(1H,brs).

EXAMPLE 46-Amino-N-(5-bromo-3-chloro-1H-indole-7-yl)-3-pyridinesulfonamide

The compound (1.00 g, 3.55 mmol) of Production Example 16 was suspendedin 25 ml of tetrahydrofuran, and then 0.86 ml (10.6 mmol) of pyridineand 718 mg (3.73 mmol) of the compound of Production Example 8 wereadded thereto under ice-cooling. After stirring at room temperature for3 hours, water was added thereto and the mixture was extracted withethyl acetate. The organic layer was washed with water and brinesuccessively, dried over magnesium sulfate and concentrated. Then, theresulting residue was purified by silica gel column chromatography togive 1.27 g of the title compound.

m.p.: It began to color at near 237° C. and decomposed at 240-242° C.(recrystallized from ethanol-water)

¹H-NMR (DMSO-d₆) δ (ppm); 6.37(1H, d, J=8.8 Hz), 6.94(2H, brs), 6.97(1H,s), 7.36(1H, s), 7.54-7.57(2H,m), 8.16(1H,d,J=2.8 Hz), 9.94(1H, brs),11.17(1H, brs).

Hydrochloride: ¹H-NMR (DMSO-d₆) δ (ppm); 6.59(1H, d, J=9.2 Hz), 7.00(1H,s), 7.40(1H, s), 7.56(1H, d, J=2.4 Hz), 7.70(1H, dd, J=9.2, 2.0 Hz),8.20(1H, d, J=2.0 Hz), 10.20(1H, brs), 11.37(1H, brs).

EXAMPLE 5 N-(3-Bromo-5-methyl-1H-indole-7-yl)-3-cyanobenzenesulfonamide

To a solution (6 ml) of 260 mg (1.16 mmol) of the compound of ProductionExample 21 in tetrahydrofuran were added 0.19 ml (2.35 mmol) of pyridineand 280 mg (1.39 mmol) of 3-cyanobenzenesulfonyl chloride underice-cooling, and the mixture was stirred at room temperature overnight.A 0.2N hydrochloric acid was added thereto, and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand brine successively, dried over magnesium sulfate and concentrated.Then, the resulting residue was purified by silica gel columnchromatography to give 360 mg of the title compound.

m.p.: It began to decompose at near 148° C. and decomposed rapidly at163-164° C. (recrystallized from ethanol-n-hexane)

¹H-NMR (DMSO-d₆) δ (ppm); 2.25(3H, s), 6.54(1H, s), 7.01(1H, s),7.42(1H, d, J=2.8 Hz), 7.71(1H, t, J=7.6 Hz), 7.93(1H, d, J=7.6 Hz),8.07-8.11(2H,m), 10.09(1H, brs), 11.04(1H, brs).

EXAMPLE 6 N-(4-Bromo-1H-indole-7-yl)-4-cyanobenzenesulfonamide

The title compound (686 mg) was obtained by treating 700 mg (2.8 mmol)of the compound of Production Example 24 and 685 mg (3.4 mmol) of4-cyanobenzenesulfonylchloride in the same manner as in Example 1.

m.p.: 214-216° C.

¹H-NMR (DMSO-d₆) δ (ppm); 6.35(1H, d, J=2.6 Hz), 6.53(1H,d,J=8.0 Hz),7.04(1H,d,J=8.0 Hz), 7.41(1H,t,J=2.8 Hz), 7.85(2H,d,J=8.0 Hz), 8.00(2H,d,J=8.0 Hz), 10.24(1H, brs), 11.19(1H, brs).

EXAMPLE 7 6Amino-N-(4-chloro-1H-indole-7-yl)-3pyridinesulfonamide

The title compound (961 mg) was obtained by treating 1330 mg (6.4 mmol)of the compound of Production Example 22 and 1000 mg (4.9 mmol) of thecompound of Production Example 12 in the same manner as in Example 1.

m.p.: 204-206° C.

¹H-NMR (DMSO-d₆) δ (ppm); 6.38(1H,d,J=9.0 Hz), 6.43(1H,t,J=2.2 Hz),6.77(1H,d,J=7.7 Hz), 6.86(2H, brs), 7.42(1H,t,J=2.6 Hz),7.56(1H,dd,J=2.6, 9.0 Hz), 8.14(1H,d,J=2.6 Hz), 9.70(1H, brs), 11.07(1H,brs).

EXAMPLE 86-Amino-N-(3-bromo-4-chloro-1H-indole-7-yl)-3-pyridinesulfonamide andHydrochloride Thereof

To a solution (10 ml) of 650 mg (2.0 mmol) of the compound of Example 7in tetrahydrofuran were added 1 ml of dimethylformamide and 359 mg (2.0mmol) of N-bromosuccinimide followed by stirring at room temperatureovernight. A 0.2N aqueous solution of hydrochloric acid was addedthereto followed by extracting with ethyl acetate. The organic layer waswashed with an aqueous solution of sodium thiosulfate, water and brinesuccessively, dried over magnesium sulfate and concentrated. Then, theresulting residue was purified by silica gel column chromatograhy togive 662 mg of the title compound.

¹H-NMR (DMSO-d₆) δ (ppm); 6.38(1H,d,J=8.8 Hz), 6.76(1H,d,J=8.4 Hz),6.88(2H, brs), 6.97(1H,d,=8.4 Hz), 7.52-7.56(2H,m) 8.12(1H,d,J=2.4 Hz),9.68(1H, brs), 11.44(1H, brs).

In 3 ml of acetone was dissolved 660 mg of the resulting title compound,0.62 ml of a 4N hydrochloric acid in ethyl acetate was added thereto andthe resulting precipitates were collected by filtration to give 590 mgof a hydrochloride of the title compound.

m.p.: It gradually began to decompose at near 267° C.

¹H-NMR (DMSO-d₆) δ (ppm); 6.65(1H,d,J=9.2 Hz), 6.78(1H,d,J=8.1 Hz),6.98(1H,d,J=8.2 Hz), 7.57(1H,d,J=2.6 Hz), 7.73(1H,dd,J=2.0, 9.0 Hz),8.15(1H,d,J=2.4 Hz), 10.00(1H, brs), 11.67(1H, brs).

EXAMPLE 9N-(3-Bromo-5-methyl-1H-indole-7-yl)-5-cyano-2-thiophenesulfonamide

Into a solution of 1.3 g (5.6 mmol) of the compound of ProductionExample 29 in 15 ml of concentrated hydrochloric acid (15 ml) wasintroduced chlorine gas under ice-cooling. After stirring for 30minutes, the reaction solution was added to ice-water followed byextracting with ethyl acetate. The organic layer was washed with waterand brine successively, dried over magnesium sulfate and concentrated.The resulting residue was added to a solution of 1.2 g (5.35 mmol) ofthe compound of Production Example 22 in 6 ml of pyridine followed bystirring at room temperature overnight. Water was added thereto followedby extracting with ethyl acetate. The organic layer was washed with a lNaqueous solution of hydrochloric acid, water and brine successively,dried over magnesium sulfate and concentrated. Then, the residue waspurified by silica gel column chromatography to give 1227 mg of thetitle compound.

m.p.: 166-169° C. (decomposition)

¹H-NMR (DMSO-d₆) δ (ppm); 2.30(3H,s), 6.65(1H, s), 7.07(1H,s),7.44(1H,s), 7.54(1H,d,J=4.0 Hz), 7.94(1H,d,J=4.0 Hz), 10.47(1H, brs),11.04(1H, brs).

EXAMPLE 102-Amino-N-(4-bromo-3-chloro-1H-indole-7-yl)-5-pyrimidinesulfonamide

To a 5 ml solution of 712 mg (2.52 mmol) of the compound of ProductionExample 33 in pyridine was added 513 mg (2.65 mmol) of the compound ofProduction Example 34, and the mixture was stirred for 15 hours. Waterwas added to the reaction solution, and then it was extracated with amixed solution of ethyl acetate and tetrahydrofuran (10:1). The organiclayer was dried over magnesium sulfate, and then concentrated andpurified by silica gel column chromatography to give 950 mg of the titlecompound.

m.p.: 285-289° C.

¹H-NMR (DMSO-d₆) δ (ppm); 6.75(1H,d,J=8.0 Hz), 7.19(1H,d,J=8.0 Hz),7.59(1H, d, J=3.0 Hz), 7.65(2H,s), 8.37(2H,s), 9.82(1H,s), 11.43(1H,s).

What is claimed:
 1. An indole compound represented by the followingformula (I), its pharmacologically acceptable salt thereof or hydratesthereof:

wherein R¹ represents hydrogen atom, a halogen atom or cyano group; R²and R³ are the same as or different from each other and each representsa hydrogen atom, a C₁-C₄ lower alkyl group or a halogen atom; R⁴represents a hydrogen atom or a C₁-C₄ lower alkyl group; the ring Arepresents a cyanophenyl group, an aminosulfonylphenyl group, or acyanothiophenyl group; and wherein (i) all of R¹, R² and R³ are nothydrogen atoms, (ii) both R² and R³ are not hydrogen atoms, (iii) thering A is not aminosulfonylphenyl group when both R¹ and R² are halogenatoms, and (iv) when the ring A is a cyanophenyl group and R¹ is a cyanogroup or a halogen group, at least one of R² and R³ is not a hydrogenatom.
 2. The indole compound as claimed in claim 1, itspharmacologically acceptable salt or hydrates thereof, wherein two ofR¹, R² and R³ are not hydrogen atoms.
 3. The indole compound as claimedin claim 1 or 2, its pharmacologically acceptable salt or hydratesthereof, wherein the ring A is cyanophenyl group or aminosulfonylphenylgroup.
 4. The indole compound as claimed in claim 1 or 2, itspharmacologically acceptable salt or hydrates thereof, wherein the ringA is cyanothiophenyl group.
 5. The indole compound as claimed in claim 1or 2, its pharmacologically acceptable salt or hydrates thereof, whereinthe ring A is cyanophenyl group.
 6. The indole compound as claimed inclaim 1, its pharmacologically acceptable salt thereof or hydratesthereof, said indole compound is selected from the group consistingof: 1) 3-Cyano-N-(3-cyano-4-methyl-1H-indol-7-yl)benzenesulfonamide, 2)N-(3-bromo-5-methyl-1H-indole-7-yl)-4-sulfamoylbenzenesulfonamide, 3)N-(3-bromo-5-methyl-1H-indole-7-yl)-3-cyanobenzenesulfonamide, 4)N-(4-bromo-1H-indole-7-yl)-4-cyanobenzenesulfonamide, and 5)N-(3-bromo-5-methyl-1H-indole-7-yl)-5-cyano-2-thiophenesulfonamide. 7.The indole compound as claimed in claim 1, its pharmacologicallyacceptable salt thereof or hydrates thereof, said indole compound isselected from the group consisting of: 1)3-Cyano-N-(3-cyano-4-methyl-1H-indol-7-yl)benzenesulfonamide, 2)N-(3-bromo-5-methyl-1H-indole-7-yl)-4-sulfamoylbenzenesulfonamide, 3)N-(3-bromo-5-methyl-1H-indole-7-yl)-3-cyanobenzenesulfonamide, and 4)N-(3-bromo-5-methyl-1H-indole-7-yl)-5-cyano-2-thiophenesulfonamide. 8.An antiangiogenic composition which comprises a pharmacologicallyeffective dose of the indole compound as claimed in claim 1, itspharmacologically acceptable salt of or hydrates thereof.
 9. Anantitumor composition for pancreatic, colon, gastric, breast, prostate,lung, or ovarian cancer, said antitumor composition comprising apharmacologically effective dose of the indole compound in claim 1, itspharmacologically acceptable salt thereof or hydrates thereof.
 10. Atherapeutic composition for pancreatic cancer which comprises the indolecompound as claimed in claim 1, its pharmacologically acceptable saltthereof or hydrates thereof in an effective amount.
 11. A therapeuticcomposition for cancer of the colon which comprises the indole compoundas claimed in claim 1, its pharmacologically acceptable salt thereof orhydrates thereof in an effective amount.
 12. A therapeutic compositionfor gastric cancer which comprises the indole compound as claimed inclaim 1, its pharmacologically acceptable salt thereof or hydratesthereof in an effective amount.
 13. A therapeutic composition for breastcancer which comprises the indole compound as claimed in claim 1, itspharmacologically acceptable salt thereof or hydrates thereof in aneffective amount.
 14. A therapeutic composition for prostatic cancerwhich comprises the indole compound as claimed in claim 1, itspharmacologically acceptable salt thereof or hydrates thereof in aneffective amount.
 15. A therapeutic composition for lung cancer whichcomprises the indole compound as claimed in claim 1, itspharmacologically acceptable salt thereof or hydrates thereof in aneffective amount.
 16. A therapeutic composition for ovarian cancer whichcomprises the indole compound as claimed in claim 1, itspharmacologically acceptable salt thereof or hydrates thereof in aneffective amount.
 17. A composition for suppressing metastasis of cancerwhich comprises the indole compound as claimed in claim 1, itspharmacologically acceptable salt thereof or hydrates thereof in aneffective amount.
 18. A therapeutic composition for diabetic retinopathywhich comprises the indole compound as claimed in claim 1, itspharmacologically acceptable salt thereof or hydrates thereof in aneffective amount.
 19. A therapeutic composition for rheumatic arthritiswhich comprises the indole compound as claimed in claim 1, itspharmacologically acceptable salt thereof or hydrates thereof in aneffective amount.
 20. A therapeutic composition for hematoma whichcomprises the indole compound as claimed in claim 1, itspharmacologically acceptable salt thereof or hydrates thereof in aneffective amount.
 21. A method for treating a disease in a patient inneed thereof against which an inhibitory effect of antiogenesis at thesite of a tumor, hematoma, rheumatic arthritis or diabetic retinopathyis effective for the treatment thereof, by administering an effectiveamount of the indole compound as claimed in claim 1, itspharmacologically acceptable salt thereof or hydrates thereof to saidpatient.
 22. The method as claimed in claim 21, wherein the tumor ispancreatic, colon, gastric, breast, prostate, lung, or ovarian.